Describing hypoglycemia — Definition or operational threshold?

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Abstract

Severe glucose deficiency leads to cerebral energy failure, impaired cardiac performance, muscle weakness, glycogen depletion, and diminished glucose production. Thus, maintenance of glucose delivery to all organs is an essential physiological function. Normal term infants have sufficient alternate energy stores and capacity for glucose production from glycogenolysis and gluconeogenesis to ensure normal glucose metabolism during the transition to extrauterine life and early neonatal period. Milk feedings particularly enhance glucose homeostasis. Energy sources often are low in preterm and growth restricted infants, who are especially vulnerable to glucose deficiency. Plasma glucose concentration is the only practical measure of glucose sufficiency, but by itself is a very limited guide. Key to preventing complications from glucose deficiency is to identify infants at risk, promote early and frequent feedings, normalize glucose homeostasis, measure glucose concentrations early and frequently in infants at risk, and treat promptly when glucose deficiency is marked and symptomatic.

Section snippets

Fetal glucose metabolism

Throughout gestation, maternal glucose provides all of the glucose for the fetus via facilitated diffusion across the placenta according to a maternal-to-fetal glucose concentration gradient [1]. Thus, glucose production in the fetus normally is non-existent or very low, although the enzymes for gluconeogenesis are present by the third month of gestation. If fetal glucose requirements cannot be met because of maternal hypoglycemia or placental insufficiency, the fetus can use alternate

Fetal glucose deficiency and development of abnormal glucose homeostasis

Despite the prevailing low glucose and insulin concentrations in the fetus with intrauterine growth restriction (IUGR), glucose uptake and utilization are maintained by augmented insulin and glucose sensitivity to promote glucose uptake into tissues [1], [2], mediated at the cellular level by increased expression of glucose- and insulin-responsive glucose transporters [3]. Chronic fetal glucose deficiency in IUGR fetuses leads to cell cycle arrest of the pancreatic β-cells, fewer β-cells, and

Glucose excess and development of abnormal glucose homeostasis

Similarly, constant, marked, and chronic hyperglycemia during gestation, as sometimes occurs in insulin dependent pregnant diabetic women, can diminish insulin production and produce peripheral insulin resistance and glucose intolerance [7]. In contrast, episodic hyperglycemia in the fetus, such as the marked meal associated hyperglycemia that occurs in gestational diabetics who produce macrosomic (obese) infants, tends to up-regulate insulin secretion and glucose disposal, particularly in

Postnatal glucose metabolism

At birth the infant is removed abruptly from its glucose supply and blood glucose concentration decreases; this phenomenon is ubiquitous among mammals and is a normal physiological function that is essential for activating glucose production by the neonate. Several hormonal and metabolic changes at birth facilitate adaptations that provide glucose to replace the supply previously received via the placenta. Induction of HGP begins shortly before term birth and is augmented after birth by

Normal glucose metabolism in newborn infants

Maintenance of glucose homeostasis depends on the balance between hepatic glucose output and peripheral glucose utilization. Steady state glucose utilization rates in term neonates are 4 to 6 mg/min/kg, about half the values of 8–9 mg/min/kg that occur at earlier gestational ages in both the fetus and preterm infant of the same gestational age [1]. Peripheral glucose utilization may increase during hypoxia due to the inherent inefficiency of anaerobic glycolysis, hyperinsulinemia which increases

Hypoglycemia — current state of the art and science

Glucose concentration is the most frequently measured laboratory value in neonatal medicine, presumably to diagnose and treat low glucose concentrations, or “hypoglycemia.” Unfortunately, there still is no research basis or consensus regarding the definition of neonatal hypoglycemia, who is at risk and when and under what circumstances, when screening should be performed, what is optimal management, what is the level and duration of neonatal hypoglycemia that might cause neurological injury

Definition of hypoglycemia

Stedman's Medical Dictionary defines hypoglycemia as an abnormally diminished content of glucose in the blood, begging the questions: Compared to what? How diminished? For how long? In relation to what other conditions or problems, such as brain blood flow, hematocrit/hemoglobin concentration, oxygen level, prior or concurrent hypoxia/ischemia, sepsis, etc.? “Abnormally” also requires discrimination between statistical and desirable concentrations, both ill-defined terms. The term

Historical and current definitions of hypoglycemia—confusion and contradiction

Hypoglycemia was defined by studies as early as 1937 as “mild”, ∼ 2.2–3.3 mmol/L (40–60 mg/dL), “moderate”, ∼ 1.1–2.2 mmol/L (20–40 mg/dL), and “extreme”, < 1.1 mmol/L (< 20 mg/dL) [14]. A variety of surveys over the past 70 years have indicated that even extremely low (0–0.5 mmol/L or 0–10 mg/dL) glucose concentrations are of limited significance, as they occur with and without clinical manifestations, usually are transient, and are easily corrected. More recently, other authors in “definitive” textbooks

Operational threshold

In response to such variable definitions, Cornblath et al. developed the concept of an “operational threshold,” defined as “that concentration of plasma or whole blood glucose at which clinicians should consider intervention, based on the evidence currently available in the literature [13].” An operational threshold is distinguished from a “treatment target”, which is somewhat higher, and a “concentration at which organ damage is known to occur,” which is somewhat lower. An “operational

Evidence-based approaches to defining hypoglycemia

Others have attempted to use evidence-based approaches to define lower limits of normal glucose concentrations, including the plasma glucose concentrations found in normal human fetuses, > 3 mmol/L [20], and the plasma glucose concentrations observed in relatively large populations of healthy full-term infants, > 1.7 mmol/L (> 30 mg/dL) in the first 24 h of life and > 2.5 mmol/L (> 45 mg/dL) after 24 h [21]. Such data depend on the physiology of the infant's adaptation to postnatal life, the character of

Clinical approaches to defining hypoglycemia

Hypoglycemia also can be defined as the glucose concentration in a neonate that is associated with clinical signs that resolve when glucose is administered. Such signs are non-specific, however, and may not be noticed initially. Attempts to quantify physiological glucose sufficiency or insufficiency have included magnetic resonance scans and measurements of cortical electrical activity and brain glucose uptake rates. Such approaches are difficult to perform and by themselves to not prove the

Importance of normal glucose concentrations in newborn infants

Human newborns are unique among mammals in having an extremely large brain relative to body size. Whole body glucose disposal correlates with brain weight and the brain requires glucose for its normal function. Furthermore, cerebral glucose utilization depends on arterial plasma glucose concentration. There is little glucose or glycogen stored in the fetal or neonatal brain, and very preterm and IUGR infants have little alternate substrates. Polycythemia, hyperviscosity, hypotension, and

Complications of hypoglycemia

Symptomatic hypoglycemic infants, primarily those with severe, protracted, and recurrent neurological conditions such as seizures and coma, plus plasma glucose concentrations of zero to 1.1 mmol/L (0–20 mg/dL) for several hours or more, have a poor prognosis, with abnormalities ranging from learning disabilities to cerebral palsy and persistent or recurrent seizure disorders, as well as mental retardation of varying degrees. Despite such evidence, the prognosis of most cases of neonatal

IUGR/SGA infants

Duvanel et al. studied the long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in preterm SGA infants, finding that 72% of the SGA infants developed hypoglycemia (< 2.6 mmol/L or 47 mg/dL) [27]. Those with recurrent neonatal hypoglycemia had smaller head circumferences at 18 months of age and lower scores on specific psychometric scores at five years. Importantly, recurrent hypoglycemia was a more predictable factor for long-term effects than the severity of a

Infants of diabetic mothers (IDMs)

In IDM's, neonatal hypoglycemia has been associated with a slightly higher incidence of long-term neurological dysfunction related to minimal brain dysfunction/deficits in attention, motor control, and perception compared with non-hypoglycemic, non-IDM control infants [28]. Specific data on the duration of hypoglycemia were not provided for the group of hypoglycemic infants.

Large for gestational aged (LGA) infants without maternal diabetes

Neurodevelopmental outcome in healthy but hypoglycemic, term, large for gestational aged (LGA) infants who are not IDMs is controversial. One study noted that “transient mild hypoglycaemia in healthy, term LGA newborns does not appear to be harmful to psychomotor development at the age of 4 years [29].” In contrast, a recent study noted a high incidence (16.2%) of hypoglycemia in admitted, non-IDM LGA full-term infants; 1.3% of those had seizures as the primary clinical manifestation [30]. As

Clinical signs (“symptoms”) of hypoglycemia

The most common, but least specific, signs associated with hypoglycemia can be seen in normal infants. They include mild to moderate changes in levels of consciousness, such as stupor or lethargy, tremulousness, and irritability. Such signs usually are relatively quickly and easily reversed with normalization of glucose supply and plasma concentration. With more serious hypoglycemia, coma and seizures occur, dependent on the duration, repetitive occurrence, and severity of hypoglycemia. Other

Treatment of hypoglycemia

Because no single concentration of plasma glucose is always associated with the appearance of clinical signs or causation of cerebral injury, treatment should be based on a flexible approach guided by clinical assessment and not solely on plasma glucose concentration. Anticipation and prevention are the key elements of intervention and management, requiring early identification of an infant at risk and institution of prophylactic measures to prevent the occurrence of hypoglycemia. In infants in

Guidelines for glucose monitoring

Neonatal glucose concentrations decrease during the first hour or two after birth, reaching a nadir around 2 h after birth, and then increase to higher and stable neonatal concentrations. There are limited data on optimal timing and intervals for glucose concentration screening. No studies have demonstrated harm from such periods of transient asymptomatic hypoglycemia during this normal postnatal period of physiological glucose homeostasis [33].

Infants at significant risk for hypoglycemia (

Complications and treatment of asymptomatic low glucose concentrations

Neonates with asymptomatic hypoglycemia usually have a normal neurodevelopmental outcome. As stated by the American Academy of Pediatrics Committee on Fetus and Newborn “No study has shown that treatment of a transiently low blood glucose level offers a better short-term or long-term outcome than the outcome resulting with no treatment… Furthermore, there is no evidence that asymptomatic hypoglycemic infants will benefit from treatment [37]…” or from supplements such as water, glucose water,

Guidelines for treatment of symptomatic, low glucose concentrations (“hypoglycemia”)

More severe hypoglycemia that is associated with significant clinical signs and pathophysiology should be treated by the “minibolus” approach: 200 mg/kg or 2 mL of D10W [10% dextrose in water] IV over 5 min followed by a constant infusion of dextrose at 6–8 mg/min/kg [39]. A constant infusion of glucose, if at high enough rates (at least 6–8 mg/min/kg), works almost as well, producing normal glucose concentrations only 5–10 min later than those produced by the minibolus, and is preferable when

Persistent hypoglycemia

The worst neurological outcomes from low glucose concentrations occur in neonates and infants with persistent and recurrent severe hypoglycemia [40]. Persistent hypoglycemia bears the associated risks of serious metabolic conditions, particularly fatty acid oxidation disorders (FAODs) and hyperinsulinism. FAODs are caused by genetic defects in the capacity to take up into the mitochondria and oxidize long chain fatty acids, leading to rapid use of glucose stores and life-threatening glucose

Summary of definition of hypoglycemia and relevance to clinical practice

Neonatal hypoglycemia represents an imbalance between glucose supply and utilization and may result from a multitude of disturbed regulatory mechanisms. A rational definition of neonatal hypoglycemia must account for the fact that acute clinical signs and long-term neurological sequelae of neonatal hypoglycemia occur with a continuum of low plasma glucose values of varied duration and severity. The permanent neurological impact of a given plasma glucose concentration in a given infant is

Acknowledgements

Dr. Rozance is supported by NIH-NICHD 1K08HD060688-01. Dr. Hay is supported by NIH-NCRR U54RR025217-01 Clinical Translational Science Award.

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